The process by which herpes simplex virus type 1 (HSV-1) establishes latency in neurons of the peripheral nervous system is poorly defined. Although considerable evidence suggests that CD8 + T cells and IFN-gamma contribute to the establishment of latency, direct evidence to support this hypothesis is lacking. In particular, a limiting factor in elucidating the mechanism(s) by which IFN-gamma could potentially inhibit viral replication is that IFN-gamma alone only marginally inhibits HSV-1 replication in vitro. Consequently, it is difficult to determine how IFN-gamma contributes to the establishment of viral latency. We have identified an unexpected event by which IFN-gamma can function m concert with IFN-beta to potently inhibit HSV-1 replication both in vitro and in vivo. The goal of the studies proposed herein is to elucidate the mechanism(s) by which IFN-beta and IFN-gamma inhibit HSV-1 replication and to identify the cellular factors that are involved in this process.